Lymphomas develop in a substantial percentage of patients infected with HIV, particularly in those in whom the viral load is poorly controlled, and treatment of these HIV-related lymphomas is extremely difficult and toxic. Thus, new approaches to the treatment of these important malignancies are much needed. While almost all central nervous system lymphomas in HIV-infected patients are associated with Epstein-Barr Virus (EBV) infection, the majority of peripheral lymphomas seen in these patients are not. Recently, our group has generated data suggesting a potential role for one of the human endogenous retroviruses, HERV-K, in the pathogenesis of HIV-related lymphoma. We have shown that RNA from HERV-K, a relatively recent entrant into the human genome that encodes two oncogenes, rec and np-9, can be found at very high levels in the plasma of patients with HIV and lymphomas. Studies at the molecular level suggest that the Tat transactivating protein of HIV may be responsible for the increase in HERV-K transcripts seen in these patients, and that the Tat effect is mediated by both upstream and downstream promoter elements. We have also shown the presence of reverse transcriptase and HERV-K RNA in plasma fractions from patients with lymphoma that also contain Gag and Env proteins. Further, we have demonstrated the presence of HERV-K virus-like particles in the plasma of these patients using immunoelectron microscopy, and have found rec and np-9 to be overexpressed in lymphoma tissues from AIDS patients. In view of the above, we hypothesize that activation of HERV-K gene expression by Tat is associated with the development of lymphoma in AIDS patients. Therefore, we will first examine how HIV infection leads to markedly increased HERV-K expression, focusing on the mechanism of Tat-mediated transcriptional activation. We will also investigate whether NP-9 and Rec regulate the growth and proliferation of lymphoma cell lines. These studies will shed light on whether HERV-K plays a role in AIDS-associated lymphoma, and whether this information can be used to better our understanding of the pathogenesis and treatment of this difficult-to-treat malignancy. PUBLIC HEALTH RELEVANCE: Patients suffering from AIDS can develop lymphoma with devastating results. These studies will help elucidate the mechanisms by which an endogenous retrovirus, HERV-K, is activated in HIV-infected individuals, cast light on the mechanisms by which these viruses could contribute to the pathogenesis of lymphoma, and perhaps suggest new therapeutic targets for these difficult-to-treat malignancies.